Bacterial infections, which cause a wide range of host immune disorders leading to local and systemic tissue damage, are still one of the main causes of patient morbidity and mortality worldwide. Treatment of bacterial infections is challenging, mainly attributed to the rapidly evolving resistance mechanisms, creating an urgent demand to develop novel antibacterial agents. Hybridization is one of the most promising strategies in the development of novel antibacterial drugs with the potential to address drug resistance since different pharmacophores in the hybrid molecules could modulate multiple targets and exert synergistic effects. Isatin, distributed widely in nature, can exert antibacterial properties by acting on diverse enzymes, proteins, and receptors. Accordingly, hybridization of isatin pharmacophores with other antibacterial pharmacophores in one molecule may provide novel antibacterial candidates with broad-spectrum activity against various pathogens, including drug-resistant forms. This review aims to outline the recent advances of natural and synthetic isatin hybrids with antibacterial potential and summarizes the structure-activity relationship (SAR) to provide an insight for the rational design of more active candidates, covering articles published between January 2012 and June 2021.